Early PD-1 expression on CD8+ T-cells and the development of a stem-like phenotype are associated with HIV slow-progression in children
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE221366 | GEO | 2023/02/01
REPOSITORIES: GEO
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Project description:A significant percentage of HIV-infected individuals experience a sharp decline in CD4+ T cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) versus chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. mRNA and miRNA expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111±22 days (Mean±SD) of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by receiver operating characteristic analysis and Kaplan-Meier survival analysis. Pathway enrichment analysis showed that genes with deregulated expression in RPs are primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a and -503) in RPs were significantly decreased compared to those in CPs (P<0.05). The decreased expression of these miRNAs was associated with rapid disease progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection. A cohort of primary HIV infected individuals with different disease outcome were enrolled in this study. We included 6 individuals with rapid disease progression (RP), seven with chronic disease progression (CP). The HIV infected individuals were never on therapy before the time of sample taken.
2013-05-01 | E-GEOD-44216 | biostudies-arrayexpress
Project description:The goal of this study was to compare the transcriptional profile between different subpopulations of CD8+ T cells in the trigeminal ganglion 8 days post HSV-1 infection. Within the HSV-1 infected TG, essentially all of the CD8+ T cells are virus specific and by using a tetramer for the immunodominant epitope from glycoprotein B (gB), we can separate the CD8+ T cell response into two populations: the gB-CD8+ T cells and the Subdom-CD8+ T cells. These populations have different levels of functionality during viral latency and express different checkpoint molecules that may influence this. Past work has shown that expression of PD-1 is associated with impaired functionality in this model and we are currently investigating the role of Tim-3, as there is little overlap in expression between Tim-3 and PD-1 and Tim-3 appears to mark functional cells when assessed by flow cytometry. By sorting cells first by using tetramer to create two populations of CD8+ T cells and then further separating these populations using expression of Tim-3 and PD-1, we have isolated subpopulations to assess what genes are up and downregulated in Tim-3+ cells compared to Tim-3- cells in each population.
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Project description:This SuperSeries is composed of the following subset Series: GSE24026: Comparison of gene expression profiles of Jurkat cells with or without PD-1 ligation GSE24081: Comparison of gene expression profiles of HIV-specific CD8 T cells from controllers and progressors Refer to individual Series
2010-10-03 | E-GEOD-24082 | biostudies-arrayexpress
Project description:The goal of this study is to characterize the transcriptional profile of PD-1+ stem-like (Tim-3-CD73+) versus terminally-differentiated (Tim-3+CD73-) CD8 T cells following two week αPD-1 blockade.
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Project description:High levels of HIV-1 replication during the chronic phase of infection are usually associated with rapid disease progression (RP). However, a minority of HIV-infected individuals remain asymptomatic and show persistently high CD4+ T cell counts despite high viremia for many years (viremic non progressors, VNP). The latter profile is reminiscent of the non-pathogenic model of SIV infection in natural hosts such as the sooty mangabey. We used various genomic approaches to examine 66 RP and 6 VNP defined according to strict criteria. RP were characterized by depletion of protective HLA alleles, enrichment of HLA alleles associated with disease progression, and a characteristic transcriptome profile of CD4+ and CD8+ T cells similar to that observed in pathogenic SIV infection of rhesus macaque. In contrast, VNPs presented lower expression of interferon stimulated genes than RP, and shared with SIV-infected sooty mangabeys a common profile of regulation of a set of genes that includes CASP1, CD38, LAG3, TNFSF13B, SOCS1 and EEF1D. The estimated 8% of RP and 0.1% of VNP in human cohorts represent two subsets of HIV-infected individuals whose analysis may inform our understanding of HIV pathogenesis. Selection criteria rapid progressors (RP): HIV seroconversion window <1 year WITH documented negative and positive serology or biological proof of primary infection. AND One of A) or B) A) >2 CD4+ T cell counts below 350 cells/µl within 3 years of seroconversion AND no subsequent rise of CD4+ T cells above 350 cells/µl in the absence of ART. B) ART initiated within 3 years of seroconversion AND CD4+ T cell count within 1 month of ART-start <350 cells/µl. Selection criteria viremic non progressors (VNP): > 3 years of follow-up AND median HIV viremia from >3 measurements >100'000 viral RNA copies/ml AND HIV viremia consistently above 10’000 copies/ml AND CD4+ T cell count above 350 cells/µl AND no ART during follow-up. Selection criteria elite/viremic controllers (EC): see Casado et al. 2010. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression. PLoS ONE 5:e11079. Total RNA from 41 samples obtained from CD4 T cells from HIV infected individuals to identify associations between gene expression and different distinct patterns of disease progression Total RNA from 38 samples obtained from CD8 T cells from HIV infected individuals to identify associations between gene expression and different distinct
2011-06-03 | E-GEOD-28128 | biostudies-arrayexpress
Project description:A significant percentage of HIV-infected individuals experience a sharp decline in CD4+ T cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) versus chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. mRNA and miRNA expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111±22 days (Mean±SD) of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by receiver operating characteristic analysis and Kaplan-Meier survival analysis. Pathway enrichment analysis showed that genes with deregulated expression in RPs are primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a and -503) in RPs were significantly decreased compared to those in CPs (P<0.05). The decreased expression of these miRNAs was associated with rapid disease progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection. The initial 347 miRNA array was performed in 11 RPs, 6 CPs and 4 corresponding matched normal controls (training group); and only the miRNAs differentially expressed between RPs and CPs (P<0.05) in training group were detected in a subsequent validation group (19 RPs versus 10 CPs). miRNAs differentially expressed in 17 early HIV infected patients (including 11 RPs and 6 CPs) and 4 healthy controls in training cohort were firstly identified. Then, miRNAs differed RPs from CPs were compared in both training and validation cohort.
2013-05-01 | E-GEOD-44332 | biostudies-arrayexpress
Project description:Ribosome assembly occurs mainly in the nucleolus yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation causes a significant decline in local translation activity and markedly reduces axon branching in the brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons.
2019-12-11 | GSE135502 | GEO
Project description:Human ribosomes are made of around 80 ribosomal proteins (RPs) and four ribosomal RNAs. To explore gene expression regulation by RPs at the transcriptional and translational levels, parallel RNA-seq and Ribo-seq were conducted in A549 cells after knockdown of individual RP.
2022-01-27 | GSE168445 | GEO
Project description:We present Chrom-Lasso, an algorithm to identify chromatin interactions from Hi-C data, which performs better in identifying functional chromatin interactions that regulates gene expression when comparing with other methods. To futher assess its performance in investigating biological questions and its ability to deal with noisy data, we use an in vitro mouse CD8+ T cell activation model to generate Hi-C data and RNA-seq data at 4 status(Tn, Teff1, Teff2, Tex) during the process of activation, and we sort T cells at different status by gating criteria as follows: Tn(CD8+, CD44-, CD62L+, at day0), Teff1(CD8+, PD-1+, TIM-3-, at day2), Teff2(CD8+, PD-1+, TIM-3-, at day5), and Tex(CD8+, PD-1+, TIM-3+, at day5), for each status, we prepare 1 Hi-C library following the in situ Hi-C prorocol, and we also prepare 3 RNA-seq libraries from 3 times of parallel experiments. Since functional interactions influence the downstream gene expression level, so the relevance between interactions detected by Chrom-Lasso and gene expression would be powerful evidence proving the capability of Chrom-Lasso in detecting functional interactions.
2020-11-30 | GSE158375 | GEO
Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes â such as BATF â that inhibit T cell function. We sorted HIV-specific CD8+ T cells from 18 progressors and 24 controllers, cohorts with a two-log difference in mean viral load
2010-10-03 | E-GEOD-24081 | biostudies-arrayexpress